Myocardial Hsp70 phosphorylation and PKC-mediated cardioprotection following exercise

Abstract

Both protein kinase C (PKC) activation and Hsp70 expression have been shown to be key components for exercise-mediated myocardial protection during ischemia-reperfusion injury. Given that Hsp70 has been shown to undergo inducible phosphorylation in striated muscle and liver, we hypothesized that PKC may regulate myocardial Hsp70 function and subsequent exercise-conferred cardioprotection through this phosphorylation. Hence, acute exercise of male Sprague-Dawley rats (30 m/min for 60 min at 2% grade) was employed to assess the role of PKC and its selected isoforms in phosphorylation of Hsp70 and protection of the myocardium during ischemia-reperfusion injury. It was observed that administration of the PKC inhibitor chelerythrine chloride (5 mg/kg) suppressed the activation of three exercise-induced PKC isoforms (PKCα, PKCδ, and PKCɛ) and attenuated the exercisemediated reduction of myocardial infarct size during ischemia-reperfusion injury. While this study also demonstrated that exercise led to an alteration in the phosphorylation status of Hsp70, this posttranslational modification appeared to be dissociated from PKC activation, as exercise-induced phosphorylation of Hsp70 was unchanged following inhibition of PKC. Taken together, these results indicate that selected isoforms of PKC play an important role in exercise-mediated protection of the myocardium during ischemia-reperfusion injury. However, exerciseinduced phosphorylation of Hsp70 does not appear to be a mechanism by which PKC induces this cardioprotective effect.

Exercise Preconditioning-Induced Early and Late Phase of Cardioprotection Is Associated With Protein Kinase C Epsilon Translocation

“…35 During exercise, CHE suppressed the activation of 3 exercise-induced PKC isoforms (PKCα, PKCδ, and PKCε) and attenuated the exercise-mediated reduction of myocardial injury size during ischemia-reperfusion injury. 18 However, recent studies by the present team have shown CHE to have no effect on the cardioprotective effects of EP, and CHE did not attenuate the expression of PKCδ or p-PKCδ Thr507 proteins during EP. 8 In fact, the influence of CHE on the cardioprotective effect is still a point of controversy.…”

Phosphoinositide 3-Kinase p110α Is a Master Regulator of Exercise-Induced Cardioprotection and PI3K Gene Therapy Rescues Cardiac Dysfunction

“…Of the mechanisms linked with exercise-induced cardiac protection, Hsp70 has been the most extensively studied, 22,24,34,35 possibly because genetic mouse models of Hsp70 loss-and gain-of-function clearly demonstrate that Hsp70 protects the heart in settings of stress. 26,36,37 In the present study, Hsp70 protein expression was elevated in hearts from Ntg mice after 4 weeks of swim training, as well as trained and untrained caPI3K mice, but not dnPI3K mice ( Figure 4A).…”

Identification of a Novel HSP70-binding Cochaperone Critical to HSP90-mediated Activation of Small Serine/Threonine Kinase

“…In the absence of SSTK, HSP70 antibody detected two bands in the immunoprecipitates, and in the presence of SSTK, the intensity of the lower band of HSP70 decreased, whereas the upper band increased significantly. HSP70 is known to undergo phosphorylation (29), and the SIP-associated HSP70 doublet bands may represent differentially phosphorylated HSP70. To determine whether SIP can directly bind HSP70, we performed binding assays using purified HSP70.…”